Publications by authors named "Daniel T Utzschneider"

20 Publications

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Editorial: Memory T Cells in Chronic Infections and Tumors.

Front Immunol 2021 17;12:656010. Epub 2021 Feb 17.

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.

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http://dx.doi.org/10.3389/fimmu.2021.656010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925626PMC
February 2021

Early precursor T cells establish and propagate T cell exhaustion in chronic infection.

Nat Immunol 2020 10 24;21(10):1256-1266. Epub 2020 Aug 24.

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.

CD8 T cells responding to chronic infections or tumors acquire an 'exhausted' state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features. Early precursor T cells showed epigenetic imprinting characteristic of T cell receptor-dependent transcription factor binding and were restricted to the generation of cells displaying exhaustion characteristics. Transcription factors BACH2 and BATF were key regulators with opposing functions in the generation of early precursor T cells. Overall, we demonstrate that exhaustion manifests first in TCF1 precursor T cells and is propagated subsequently to the pool of antigen-specific T cells.
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http://dx.doi.org/10.1038/s41590-020-0760-zDOI Listing
October 2020

Human effector T cells express TOX-Not so "TOX"ic after all.

Sci Immunol 2020 07;5(49)

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.

TOX expression is not restricted to exhausted T cells but a characteristic of all human effector CD8 T cells.
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http://dx.doi.org/10.1126/sciimmunol.abc8272DOI Listing
July 2020

MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

Sci Adv 2019 12 11;5(12):eaaw1715. Epub 2019 Dec 11.

Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

Follicular helper T (T) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating T cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated T cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced T cell responses. Mechanistically, miR-23~27~24 clusters coordinately control T cells through targeting a network of genes that are crucial for T cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in T cell development. TOX is highly up-regulated in both mouse and human T cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in T cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal T cell responses for resultant humoral immunity.
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http://dx.doi.org/10.1126/sciadv.aaw1715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905868PMC
December 2019

Precursor exhausted T cells: key to successful immunotherapy?

Nat Rev Immunol 2020 02 7;20(2):128-136. Epub 2019 Oct 7.

Department of Microbiology & Immunology Melbourne, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.

Cytotoxic T cell immunity in response to chronic infections and tumours is maintained by a specialized population of CD8 T cells that exhibit hallmarks of both exhausted and memory cells and give rise to terminally differentiated exhausted effector cells that contribute to viral or tumour control. Importantly, recent work suggests these cells, which we refer to as 'precursor exhausted' T (T) cells, are responsible for the proliferative burst that generates effector T cells in response to immune checkpoint blockade targeting programmed cell death 1 (PD1), and increased T cell frequencies have recently been linked to increased patient survival. We believe the recent discovery of T cells not only represents a paradigm shift in our understanding of the mechanisms that maintain CD8 T cell responses in chronic infections and tumours but also opens up unexpected avenues for the development of new and innovative therapeutic approaches. In this Opinion article, we discuss the differentiation and function of T cells and suggest that targeting these cells may be key for successful immunotherapy.
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http://dx.doi.org/10.1038/s41577-019-0223-7DOI Listing
February 2020

TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection.

Nature 2019 07 17;571(7764):265-269. Epub 2019 Jun 17.

Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential. This process, known as T cell exhaustion or dysfunction, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1). The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1 self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.
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http://dx.doi.org/10.1038/s41586-019-1326-9DOI Listing
July 2019

Active Maintenance of T Cell Memory in Acute and Chronic Viral Infection Depends on Continuous Expression of FOXO1.

Cell Rep 2018 03;22(13):3454-3467

Molecular Biology Section, Division of Biological Sciences, UC San Diego, La Jolla, CA 92093, USA; Cellular and Molecular Medicine, UC San Diego, La Jolla, CA 92093, USA. Electronic address:

Immunity following an acutely resolved infection or the long-term equipoise of chronic viral infections often depends on the maintenance of antigen-specific CD8 T cells, yet the ongoing transcriptional requirements of these cells remain unclear. We show that active and continuous programming by FOXO1 is required for the functional maintenance of a memory population. Upon Foxo1 deletion following resolution of an infection, memory cells rapidly lost their characteristic gene expression, gradually declined in number, and were impaired in self-renewal. This was extended to chronic infections, as a loss of FOXO1 during a persistent viral infection led to a rapid decline of the TCF7 (a.k.a. TCF1)-expressing memory-like subset of CD8 T cells. We further establish FOXO1 regulation as a characteristic of human memory CD8 T cells. Overall, we show that the molecular and functional longevity of a memory T cell population is actively maintained by the transcription factor FOXO1.
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http://dx.doi.org/10.1016/j.celrep.2018.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942184PMC
March 2018

Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8 T cells.

J Exp Med 2018 02 27;215(2):575-594. Epub 2017 Dec 27.

Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla CA

Upon infection with an intracellular pathogen, cytotoxic CD8 T cells develop diverse differentiation states characterized by function, localization, longevity, and the capacity for self-renewal. The program of differentiation is determined, in part, by FOXO1, a transcription factor known to integrate extrinsic input in order to specify survival, DNA repair, self-renewal, and proliferation. At issue is whether the state of T cell differentiation is specified by initial conditions of activation or is actively maintained. To study the spectrum of T cell differentiation, we have analyzed an infection with mouse cytomegalovirus, a persistent-latent virus that elicits different cytotoxic T cell responses characterized as acute resolving or inflationary. Our results show that FOXO1 is continuously required for all the phenotypic characteristics of memory-effector T cells such that with acute inactivation of the gene encoding FOXO1, T cells revert to a short-lived effector phenotype, exhibit reduced viability, and manifest characteristics of anergy.
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http://dx.doi.org/10.1084/jem.20170697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789410PMC
February 2018

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis.

Proc Natl Acad Sci U S A 2017 05 24;114(19):4987-4992. Epub 2017 Apr 24.

Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland;

The presence of the endogenous RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured ( ) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing ( ) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ-deficient mice promoted parasite dissemination to secondary sites, reproducing the metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis.
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http://dx.doi.org/10.1073/pnas.1621447114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441690PMC
May 2017

Exacerbated Leishmaniasis Caused by a Viral Endosymbiont can be Prevented by Immunization with Its Viral Capsid.

PLoS Negl Trop Dis 2017 01 18;11(1):e0005240. Epub 2017 Jan 18.

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

Recent studies have shown that a cytoplasmic virus called Leishmaniavirus (LRV) is present in some Leishmania species and acts as a potent innate immunogen, aggravating lesional inflammation and development in mice. In humans, the presence of LRV in Leishmania guyanensis and in L. braziliensis was significantly correlated with poor treatment response and symptomatic relapse. So far, no clinical effort has used LRV for prophylactic purposes. In this context, we designed an original vaccine strategy that targeted LRV nested in Leishmania parasites to prevent virus-related complications. To this end, C57BL/6 mice were immunized with a recombinant LRV1 Leishmania guyanensis viral capsid polypeptide formulated with a T helper 1-polarizing adjuvant. LRV1-vaccinated mice had significant reduction in lesion size and parasite load when subsequently challenged with LRV1+ Leishmania guyanensis parasites. The protection conferred by this immunization could be reproduced in naïve mice via T-cell transfer from vaccinated mice but not by serum transfer. The induction of LRV1 specific T cells secreting IFN-γ was confirmed in vaccinated mice and provided strong evidence that LRV1-specific protection arose via a cell mediated immune response against the LRV1 capsid. Our studies suggest that immunization with LRV1 capsid could be of a preventive benefit in mitigating the elevated pathology associated with LRV1 bearing Leishmania infections and possibly avoiding symptomatic relapses after an initial treatment. This novel anti-endosymbiotic vaccine strategy could be exploited to control other infectious diseases, as similar viral infections are largely prevalent across pathogenic pathogens and could consequently open new vaccine opportunities.
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http://dx.doi.org/10.1371/journal.pntd.0005240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242429PMC
January 2017

T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections.

Immunity 2016 08;45(2):415-27

Ludwig Center for Cancer Research, Department of Fundamental Oncology, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address:

Chronic infections promote the terminal differentiation (or "exhaustion") of T cells and are thought to preclude the formation of memory T cells. In contrast, we discovered a small subpopulation of virus-specific CD8(+) T cells that sustained the T cell response during chronic infections. These cells were defined by, and depended on, the expression of the transcription factor Tcf1. Transcriptome analysis revealed that this population shared key characteristics of central memory cells but lacked an effector signature. Unlike conventional memory cells, Tcf1-expressing T cells displayed hallmarks of an "exhausted" phenotype, including the expression of inhibitory receptors such as PD-1 and Lag-3. This population was crucial for the T cell expansion that occurred in response to inhibitory receptor blockade during chronic infection. These findings identify a memory-like T cell population that sustains T cell responses and is a prime target for therapeutic interventions to improve the immune response in chronic infections.
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http://dx.doi.org/10.1016/j.immuni.2016.07.021DOI Listing
August 2016

High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival.

J Exp Med 2016 08 25;213(9):1819-34. Epub 2016 Jul 25.

Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland

Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment.
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http://dx.doi.org/10.1084/jem.20150598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995073PMC
August 2016

Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs.

Neuron 2016 05 21;90(3):535-50. Epub 2016 Apr 21.

Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.
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http://dx.doi.org/10.1016/j.neuron.2016.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860075PMC
May 2016

NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions.

Nat Commun 2016 Feb 10;7:10554. Epub 2016 Feb 10.

Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland.

NLRC5 is a transcriptional regulator of MHC class I (MHCI), which maintains high MHCI expression particularly in T cells. Recent evidence highlights an important NK-T-cell crosstalk, raising the question on whether NLRC5 specifically modulates this interaction. Here we show that NK cells from Nlrc5-deficient mice exhibit moderate alterations in inhibitory receptor expression and responsiveness. Interestingly, NLRC5 expression in T cells is required to protect them from NK-cell-mediated elimination upon inflammation. Using T-cell-specific Nlrc5-deficient mice, we show that NK cells surprisingly break tolerance even towards 'self' Nlrc5-deficient T cells under inflammatory conditions. Furthermore, during chronic LCMV infection, the total CD8(+) T-cell population is severely decreased in these mice, a phenotype reverted by NK-cell depletion. These findings strongly suggest that endogenous T cells with low MHCI expression become NK-cell targets, having thus important implications for T-cell responses in naturally or therapeutically induced inflammatory conditions.
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http://dx.doi.org/10.1038/ncomms10554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749981PMC
February 2016

Immune-surveillance through exhausted effector T-cells.

Curr Opin Virol 2016 Feb 29;16:49-54. Epub 2016 Jan 29.

Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie, Freiburg, Germany.

Pathogens such as the human immunodeficiency virus (HIV), the hepatitis B and C virus (HBV, HCV) and certain strains of the rodent lymphocytic choriomeningitis virus (LCMV) establish a state of persisting viral replication. This occurs besides strong adoptive immune responses and the induction of large numbers of activated pathogen-specific T-cells. The failure of the immune system to clear these viruses is typically attributed to a loss of effector T-cell function-a phenomenon referred to as T-cell exhaustion. Though largely accepted, this loss of function concept is being more and more challenged by comprehensive clinical and experimental observations which highlight that T-cells in chronic infections are more functional than previously considered. Here, we highlight examples that demonstrate that such T-cells mediate a profound form of immune-surveillance. We also briefly discuss the opportunities and limitations of employing 'exhausted' T-cells for therapeutic purposes.
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http://dx.doi.org/10.1016/j.coviro.2016.01.002DOI Listing
February 2016

Structure-function analyses of human kallikrein-related peptidase 2 establish the 99-loop as master regulator of activity.

J Biol Chem 2014 Dec 16;289(49):34267-83. Epub 2014 Oct 16.

From the Division of Structural Biology, Department of Molecular Biology, University of Salzburg, A-5020 Salzburg, Austria,

Human kallikrein-related peptidase 2 (KLK2) is a tryptic serine protease predominantly expressed in prostatic tissue and secreted into prostatic fluid, a major component of seminal fluid. Most likely it activates and complements chymotryptic KLK3 (prostate-specific antigen) in cleaving seminal clotting proteins, resulting in sperm liquefaction. KLK2 belongs to the "classical" KLKs 1-3, which share an extended 99- or kallikrein loop near their non-primed substrate binding site. Here, we report the 1.9 Å crystal structures of two KLK2-small molecule inhibitor complexes. In both structures discontinuous electron density for the 99-loop indicates that this loop is largely disordered. We provide evidence that the 99-loop is responsible for two biochemical peculiarities of KLK2, i.e. reversible inhibition by micromolar Zn(2+) concentrations and permanent inactivation by autocatalytic cleavage. Indeed, several 99-loop mutants of KLK2 displayed an altered susceptibility to Zn(2+), which located the Zn(2+) binding site at the 99-loop/active site interface. In addition, we identified an autolysis site between residues 95e and 95f in the 99-loop, whose elimination prevented the mature enzyme from limited autolysis and irreversible inactivation. An exhaustive comparison of KLK2 with related structures revealed that in the KLK family the 99-, 148-, and 220-loop exist in open and closed conformations, allowing or preventing substrate access, which extends the concept of conformational selection in trypsin-related proteases. Taken together, our novel biochemical and structural data on KLK2 identify its 99-loop as a key player in activity regulation.
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http://dx.doi.org/10.1074/jbc.M114.598201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256358PMC
December 2014

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Nat Rev Immunol 2014 11 26;14(11):768-74. Epub 2014 Sep 26.

Swiss Vaccine Research Institute, Centre des laboratoires d'Epalinges, 1066 Epalinges, Switzerland, and the Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland.

Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors.
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http://dx.doi.org/10.1038/nri3740DOI Listing
November 2014

T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion.

Nat Immunol 2013 Jun 5;14(6):603-10. Epub 2013 May 5.

Swiss Vaccine Research Institute, Epalinges, Switzerland.

During chronic infection, pathogen-specific CD8(+) T cells upregulate expression of molecules such as the inhibitory surface receptor PD-1, have diminished cytokine production and are thought to undergo terminal differentiation into exhausted cells. Here we found that T cells with memory-like properties were generated during chronic infection. After transfer into naive mice, these cells robustly proliferated and controlled a viral infection. The reexpanded T cell populations continued to have the exhausted phenotype they acquired during the chronic infection. Thus, the cells underwent a form of differentiation that was stably transmitted to daughter cells. We therefore propose that during persistent infection, effector T cells stably differentiate into a state that is optimized to limit viral replication without causing overwhelming immunological pathology.
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http://dx.doi.org/10.1038/ni.2606DOI Listing
June 2013

MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer.

Immunity 2013 Apr;38(4):742-53

Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.

MicroRNAs (miRNAs) regulate the function of several immune cells, but their role in promoting CD8(+) T cell immunity remains unknown. Here we report that miRNA-155 is required for CD8(+) T cell responses to both virus and cancer. In the absence of miRNA-155, accumulation of effector CD8(+) T cells was severely reduced during acute and chronic viral infections and control of virus replication was impaired. Similarly, Mir155(-/-) CD8(+) T cells were ineffective at controlling tumor growth, whereas miRNA-155 overexpression enhanced the antitumor response. miRNA-155 deficiency resulted in accumulation of suppressor of cytokine signaling-1 (SOCS-1) causing defective cytokine signaling through STAT5. Consistently, enforced expression of SOCS-1 in CD8(+) T cells phenocopied the miRNA-155 deficiency, whereas SOCS-1 silencing augmented tumor destruction. These findings identify miRNA-155 and its target SOCS-1 as key regulators of effector CD8(+) T cells that can be modulated to potentiate immunotherapies for infectious diseases and cancer.
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http://dx.doi.org/10.1016/j.immuni.2012.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788592PMC
April 2013

Functional avidity: a measure to predict the efficacy of effector T cells?

Clin Dev Immunol 2012 20;2012:153863. Epub 2012 Nov 20.

Divisions of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland.

The functional avidity is determined by exposing T-cell populations in vitro to different amounts of cognate antigen. T-cells with high functional avidity respond to low antigen doses. This in vitro measure is thought to correlate well with the in vivo effector capacity of T-cells. We here present the multifaceted factors determining and influencing the functional avidity of T-cells. We outline how changes in the functional avidity can occur over the course of an infection. This process, known as avidity maturation, can occur despite the fact that T-cells express a fixed TCR. Furthermore, examples are provided illustrating the importance of generating T-cell populations that exhibit a high functional avidity when responding to an infection or tumors. Furthermore, we discuss whether criteria based on which we evaluate an effective T-cell response to acute infections can also be applied to chronic infections such as HIV. Finally, we also focus on observations that high-avidity T-cells show higher signs of exhaustion and facilitate the emergence of virus escape variants. The review summarizes our current understanding of how this may occur as well as how T-cells of different functional avidity contribute to antiviral and anti-tumor immunity. Enhancing our knowledge in this field is relevant for tumor immunotherapy and vaccines design.
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http://dx.doi.org/10.1155/2012/153863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511839PMC
August 2013